ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.982G>C (p.Gly328Arg) (rs104894832)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000179268 SCV000231490 pathogenic not provided 2015-03-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780293 SCV000917446 likely pathogenic Fabry disease 2018-06-27 criteria provided, single submitter clinical testing Variant summary: GLA c.982G>C (p.Gly328Arg) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 178747 control chromosomes. c.982G>C has been reported in the literature in two individuals affected with Fabry Disease (Lukas_2016, Wijburg_2015). In addition, multiple publications cite p.Gly328Arg in patients with Fabry disease, however a different nucleotide change resulting in the same amino acid change also has been reported (c.982G>A), and these publications do not specify the nucleotide change (Biancini_2012, Frustaci_2001, Lenders_2016). These data indicate that the variant is likely to be associated with disease and reflect the functional importance of this residue.. A functional in vitro study in which enzyme activity was tested in HEK-293H cells expressing the variant of interest showed completely absent enzyme activity, and plasma lyso-Gb3 levels were significantly elevated in the patient carrying the variant (Lukas_2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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